Eligibility Criteria in Clinical Trials: PARP Inhibitors

July 1, 2013 7:59 pm

The following article is provided by The Clearity Foundation to support women with ovarian cancer and their families. Learn more about The Clearity Foundation and the services we provide directly to women as they make treatment decisions and navigate emotional impacts of their diagnosis.

Eligibility Criteria in Clinical Trials: PARP Inhibitors

By: Cory Bentley, PhD

Clearity first reported on drugs inhibiting PARP (Poly-ADP ribose polymerase), an important enzyme for tumor cell proliferation and survival, in its September 2010 patient newsletter.  At that time, PARP inhibitors were just entering clinical trials and only two trials were recruiting patients. Now, thanks to promising results from the early trials, multiple PARP inhibitors are moving forward in ovarian cancer clinical trials and are also being evaluated in other cancer types. PARP inhibitors have proven most effective in patients with a mutation in one of the BRCA genes, but tumors with mutations in other DNA repair pathways may also be sensitive to PARP inhibition. A quick search of Clearity’s clinical trial search engine for ovarian cancer trials using “PARP1/2” as the search term in the targeted drug field pulls up 20 clinical trials. Most are phase I studies but there will soon be new phase II and even phase III trials added.

In fact, four companies have indicated that they are moving PARP inhibitors into pivotal phase III trials for ovarian cancer soon, including Abbott, AstraZeneca, Clovis, and Tesaro.  All of these trials will evaluate the efficacy of these inhibitors as a maintenance therapy. As described in the accompanying article, maintenance therapy is given to patients that have responded to their previous treatment with the aim of prolonging their time to recurrence or progression.  For Abbott’s veliparib, the phase III study will be in newly diagnosed patients with stage 1C-IV high grade serous cancer in combination with platinum/paclitaxel with randomization to the maintenance therapy with either veliparib or placebo.  For the other three PARP inhibitor trials, the maintenance therapy is for women whose cancer recurred and responded again to platinum-based treatment.

Tesaro’s President, Mary Lynn Hedley, PhD talked with Clearity about the phase III trial for niraparib. The niraparib trial will have many study sites across North America. Patients will be randomized into the study drug group or placebo group 2:1, meaning that for every three patients that enroll, two will get the study drug and one will get the placebo.  Dr. Hedley explains that this 2:1 design study will take longer to complete because more patients are necessary for the trial, but she knows that it is important to patients that they have a good chance to be on the study drug. The niraparib trial will take patients regardless of their BRCA mutation status because some studies indicate that patients with high grade serous ovarian cancer can have mutations other than BRCA in DNA repair pathways that make them equally susceptible to PARP inhibitors.

AstraZeneca’s PARP inhibitor, olaparib, will be tested in phase III studies this year, but will specifically focus on patients who have BRCA mutations, based on good responses in those patients in their phase II studies.  According to the updated analysis for their phase II maintenance therapy study presented at the annual meeting of the American Society of Clinical Oncology (ASCO) on June 2, women with BRCA mutations (germline or tumor) had a significantly improved time to tumor progression: 11.3 months on olaparib vs. 4.3 months on placebo.

Clovis is also planning to start a phase III trial this year with its PARP inhibitor, rucaparib, for platinum-sensitive high grade serous ovarian cancer.  This trial will have a similar design to the one described for niraparib, but will additionally stratify patients based on BRCA status as well as evidence for other biomarkers associated with DNA repair defects.

It is clear that all of these phase III trials are paying close attention to patients’ tumor blueprint either to decide on enrollment or to help further identify which patients are most likely to respond to the respective drugs.

Apart from a patient’s tumor molecular profile or blueprint, many other factors determine patient eligibility, including the number and types of prior chemotherapies and other treatments, stage of disease, and health factors. For this reason, it is imperative that patients consider clinical trials early in their treatment, so that they do not inadvertently make themselves ineligible for participation in promising trials. Patients and their doctors have to be one step ahead of their cancers as they map out possible treatment paths.  Clearity can help by using each patient’s own blueprint to identify possible options that include both approved treatments and clinical trials. A number of Clearity’s patients have participated in PARP inhibitor trials.

The current and upcoming PARP inhibitor trials hold the promise of new treatment options for ovarian cancer patients. These studies will also bring a wealth of new data that will help guide future patients and their doctors to make informed treatment choices.

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